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Flu Pandemic Mitigation - Medicine

The single best way to prevent influenza is to get vaccinated each fall. In the absence of vaccine, however, there are other ways to protect against influenza. Four antiviral drugs (amantidine, rimantidine, oseltamivir and zanamivir) are approved and commercially available for use in treating influenza. Three of them (amantidine, rimantidine, and oseltamivir) are approved for prevention (chemoprophylaxis) against influenza. All of these drugs are prescription drugs, and a doctor should be consulted before their use.

Do not take antibiotics for the flu. They won't work against the flu virus.

Flu Medications

Antiviral chemoprophylaxis is also effective in preventing influenza or reducing the severity of illness. As with vaccine, in studies of healthy young adults antiviral drugs were generally 70 to 90 percent effective in preventing influenza. There are two classes of antiviral agents: the M2 inhibitors, amantadine (Symmetrel®) and rimantadine (Flumadine®); and the neuraminidase inhibitors, oseltamivir (Tamiflu®) and zanamivir (Relenza ®).

Amantadine and rimantadine are thought to interfere with influenza A virus M2 protein, a membrane ion channel protein, and inhibit virus uncoating, which inhibits virus replication, resulting in decreased viral shedding. The M2 inhibitors are effective against most strains of influenza A but are not effective against influenza B.

Some strains of influenza A, including the current H5N1 strain posing a potential pandemic risk, are resistant to the M2 inhibitors. Influenza virus isolates from some patients in Vietnam in the winter of 2004 were found to be resistant to the older, more affordable anti-influenza drugs: amantidine and rimantadine. However, these viruses were still sensitive to the newer and expensive oral drug oseltamivir (Tamiflu).

Zanamivir and oseltamivir block the active site of the influenza viral enzyme neuraminidase, which is common to both influenza A and influenza B viruses. This effect results in viral aggregation at the host cell surface and reduces the number of viruses released from the infected cell. The neuraminidase inhibitors are effective against both influenza A and influenza B. Resistance to the neuraminidase inhibitors has been rare, but recent reports from Asia indicate that some strains of H5N1 may be partially resistant to these agents as well.

Neuraminidase cleaves terminal sialic acid residues from carbohydrate moieties on the surfaces of host cells and influenza virus envelopes; this process promotes the release of progeny viruses from infected cells. Neuraminidase inhibitors are analogues of sialic acid. Their proposed mechanism of action is to block the active site of neuraminidase and leave uncleaved sialic acid residues on the surfaces of host cells and influenza viral envelopes. Viral hemagglutinin binds to the uncleaved sialic acid residues; the result is viral aggregation at the host cell surface and a reduction in the amount of virus that is released and can infect other cells.

Antiviral medications for treatment or prevention of pandemic influenza could have an important interim role, but may also be in short supply. Two groups of antiviral drugs are available for the treatment and prophylaxis of influenza. These are the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir and zanamivir). The adamantanes may be effective against pandemic strains, but concern exists about adverse reactions and the development of antiviral resistance. Resistance to amantadine has been demonstrated in a number of avian H5 strains and its use for treatment of influenza is not recommended.

The primary source of antiviral drugs for a pandemic response will be the supply of antiviral drugs that have been stockpiled. Before annual influenza seasons about 2 million treatment courses of oseltamivir are available in the US. US-based production of oseltamivir is being established; expected capacity is projected at about 1.25 million courses per month.

Oseltamivir (trade name Tamiflu) is a well tolerated orally active neuraminidase inhibitor which significantly reduces the duration of symptomatic illness and hastens the return to normal levels of activity when initiated promptly in patients with naturally acquired influenza. It therefore represents a useful therapeutic alternative to zanamivir (especially in patients who prefer oral administration or who have an underlying respiratory disorder) and the M2 inhibitors amantadine and rimantadine (because of its broader spectrum of anti-influenza activity and lower likelihood of resistance) in patients with influenza. In addition, although annual vaccination remains the best means of influenza prevention, there may be a place for oseltamivir in providing household prophylaxis or adjunctive prophylaxis in high-risk vaccinated patients during an outbreak of the disease.

The approximate 10-fold higher frequency of resistance emergence in children compared to adults treated with oseltamivir is likely indicative of the outcomes during pandemic influenza. Patterns of cross-resistance vary with particular neuraminidase mutations and virus type, such that zanamivir retains full activity against the most commonly recognized N1 mutation that confers high-level resistance to oseltamivir. Since H5N1 strain would likely show this mutation if sufficient selective drug pressure, some have argued that more emphasis on potential use of zanamivir and development of alternative agents is appropriate.

Inhaled zanamivir is not approved for prophylaxis in the US -- although it is approved for this indication in other countries and is clearly effective. Zanamivir is a neuraminidase inhibitor taken using an inhaler (diskhaler). Virtually none is absorbed from the respiratory tract. It is licensed for the treatment of influenza A and B in people aged 12 or older, if given within 48 hours of onset of symptoms and when influenza is circulating in the community. Zanamivir is contra-indicated in women who are pregnant or breast-feeding and should be used cautiously in people who have unstable chronic illness or compromised immune systems. The dose is 10mg by inhalation twice daily for 5 days. Some elderly and disabled people may have difficulty using the diskhaler.

Rimantadine {trade name Flumadine}is used to prevent and treat infections caused by influenza A virus. This medication is sometimes prescribed for other uses. Rimantadine will not work for colds, other types of flu, or other virus infections. Rimantadine comes as a tablet and a liquid to take by mouth. It usually is taken once or twice a day for 2-12 weeks. Although rimantadine is approved only for prophylaxis of infection among children, certain specialists in the management of influenza consider it appropriate for treatment among children. This medicine may cause some people to become dizzy or confused, or to have trouble concentrating.

Amantadine is an 'M2 inhibitor' active only against influenza A (it has no activity against influenza B). It is taken orally, excreted through the kidneys and licensed for the treatment and prophylaxis of influenza A. Amantadine is not licensed in the UK for use in children under 10 and contraindicated in individuals subject to convulsions, a history of gastric ulceration/severe renal disease and when pregnant or breast-feeding. It should be used cautiously in individuals who are in confused or hallucinatory states, suffer underlying psychiatric conditions, or have liver, kidney or cardiovascular disorders. It has a number of drug interactions and some strains of influenza A virus rapidly develop resistance when exposed to amantadine. This is reported to be more common when the agent is used for both prophylaxis and treatment in the same household. The treatment dose is 100mg daily for 4-5 days for treatment and 100mg for up to 6 weeks for prophylaxis. Higher incidence of adverse reactions associated with higher doses have been reported. Authorities E do not recommend the use of amantadine for treatment or prevention of seasonal influenza, but it may have a place, particularly in prophylaxis, in an influenza pandemic, if the pandemic virus is susceptible.

There are many issues around the use of antiviral medications, one of the main ones being that they do not exist in large quantities. Although they are not used commonly during normal epidemic years, it is likely that in a pandemic scenario there will more demand for such drugs. Given the very limited supply, difficult issues arise in the area of prioritizing them and also with respect to determining how much of the available supply should be used for prophylaxis and for treatment. At present there is a small national stockpile of antiviral medications, and it is possible that the stockpile will be larger in the future. It is important to realize that while antiviral medications may be beneficial to some in terms of averting infection or reducing complications, they may not be able to markedly alter the course of a pandemic at a population level.

Antivirals are most efficiently used for treatment. If the available stock is less than the clinical attack rate it will be necessary to limit treatment to priority groups. For a given stockpile, the stock available for use in treatment will depend on how much is used for prophylaxis (be it targeted prophylaxis for containment, or prophylaxis of essential workers or their contacts).

Although the main purpose of antiviral treatment is to reduce the severity of the disease, treating all clinical cases with antivirals might also decrease the overall attack rate. There is considerable uncertainty as to the extent of the reduction possible. Some models suggest a reduction of up to one third. This suggests, for example, that treating all cases in an outbreak for which the attack rate would be 50% without treatment might only require enough antiviral courses for ~35% of the population.

Personal stockpiles are not recommended in the draft national pandemic preparedness plan for use of antiviral drugs during a pandemic. The plan calls for use of limited supplies of antiviral drugs for treatment rather than prophylaxis and for targeting priority groups (i.e., persons requiring hospitalization, persons at risk for severe influenza) for antiviral use during a pandemic. Personal stockpiles could make less drug available in the private sector for treatment of priority groups should a pandemic arise in the near future.

Personal stockpiling may result in shortages of drug for use in treatment and prevention of seasonal influenza infections. There is no pandemic occurring currently. Although many experts are concerned that the expanding avian influenza A H5N1 outbreak may result in a pandemic, it is not known when the pandemic might begin, the specific virus that will ultimately emerge, and the associated health impacts. The drug might not be effective in preventing severe illness or death and the optimal dose is not known for the current avian H5N1 strain.

How will persons know when to initiate treatment? The drug will be wasted if taken for non-influenza infection or when a pandemic is not occurring. If the virus is susceptible, the drug should be administered early in the course of illness when symptoms may be nonspecific. The shelf life is limited and may give false assurance if relied upon after expiration or after suboptimal storage conditions. Inequitable distribution: The drug is expensive and if shortages occur, persons who do not choose to stockpile or cannot afford to stockpile might subsequently have less access to the drug.

IgG Antibodies

If a pandemic were to occur, not only would the world need a preventive vaccine, it would also need effective treatments. A quick jolt of antibodies able to ward off a deadly flu strain could help protect individuals already exposed or at risk of exposure. NIAID-funded researchers Stephen Cape, Ph.D., and Robert Sievers, Ph.D., of Aktiv-Dry, a biotechnology firm in Boulder, CO, think they have the answer: flu-fighting IgG antibodies that are inhaled as a dry powder rather than injected. "In earlier studies, IgG antibodies have proven effective in fighting influenza in mice when delivered into the nasal cavity or the lungs," says Dr. Cape. "In powder form, they have the potential to be very useful in a global pandemic."

According to the two researchers, one of the foremost benefits of powdered influenza antibodies is their stability at room temperature, allowing them to be stored for long periods of time in the field. "This would be particularly useful in developing countries, where refrigeration may not be available," adds Dr. Sievers. In addition, the size of the particles is extremely small. One puff could deliver a high concentration of antibodies to the lungs with fewer side effects than an injection into muscle.

The technology used to produce the powdered antibodies employs carbon dioxide, which turns the antibodies, mixed in solution, into a fine mist. The mist is later dried in the presence of warm nitrogen to yield a powder. After the powder has been tested for optimal particle size and antigen-binding ability, it will be sprayed into the lungs of mice to assess the level of protection the antibodies provide when the mice are exposed to influenza.

Herbal Remedies

There is adequate substantiation for the claim that Sambucol is effective in reducing the symptoms and duration of influenza A and B. Sambucus nigra L. products - Sambucol - are based on a standardized black elderberry extract. They are natural remedies with antiviral properties, especially against different strains of influenza virus. Sambucol was shown to be effective in vitro against 10 strains of influenza virus. In a double-blind, placebo-controlled, randomized study, Sambucol reduced the duration of flu symptoms to 3-4 days. Convalescent phase serum showed a higher antibody level to influenza virus in the Sambucol group, than in the control group. Sambucol Elderberry Extract and its formulations activate the healthy immune system by increasing inflammatory cytokine production. Sambucol might therefore be beneficial to the immune system activation and in the inflammatory process in healthy individuals or in patients with various diseases. Sambucol could also have an immunoprotective or immunostimulatory effect when administered to cancer or AIDS patients, in conjunction with chemotherapeutic or other treatments.

Curcumin is a spice principle in, and constitutes approximately 4 percent of, turmeric, the ingredient that gives curry its yellow hue. Some have speculated that curcumin in high doses might inhibits the cytokine storms that are a leading cause of death from pandemic influenza, but this remains speculation. Curcumin's immuno-modulating and anti-oxidant activities suggest that it might be a useful adjunct in the treatment of illnesses characterized by inflammation. NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types.



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Page last modified: 13-07-2011 12:49:32 ZULU